Heterochromatin instability and misregulation of noncoding RNA in cancer
癌症中异染色质的不稳定性和非编码 RNA 的失调
基本信息
- 批准号:8005196
- 负责人:
- 金额:$ 4.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-12-01 至 2013-11-30
- 项目状态:已结题
- 来源:
- 关键词:Biological MarkersCancer PrognosisCancer cell lineCell divisionCellsCellular biologyChromosomesCommitDNADataEarly DiagnosisElementsEpigenetic ProcessEventFunctional RNAGeneticHeterochromatinHistocompatibility TestingHuman GenomeIndividualKnowledgeLinkLocationMalignant NeoplasmsMethylationPathologistPluripotent Stem CellsPublic HealthRNARegulationResearchSamplingSatellite DNASatellite RNASomatic CellStagingStem cellsSurveysTumor Suppressor GenesUntranslated RNAUp-Regulationbasecancer cellembryonic stem cellhuman embryonic stem celloverexpressionpublic health relevancetumortumor progression
项目摘要
DESCRIPTION (provided by applicant): Nearly 50% of the human genome consists of non-coding DNA elements, including several types of tandem satellite repeats in large blocks at the centric and pericentric regions of chromosomes. While satellites were long thought to be silent, recent evidence indicates that satellite repeats can be expressed, but the extent and regulation of their expression or their potential function(s) remain to be elucidated. Due to their critical location within regions vital for cell division, it is expected that tight regulation of these sequences is essential for both epigenetic and genetic stability. This proposal will build on strong preliminary results suggesting satellite RNA regulation may be important to both stem cell and cancer cell biology. Aim 1 will further build upon preliminary data that expression of centromeric satellites is upregulated during differentiation of embryonic stem cells. Surprisingly, our recent findings also indicate that centromeric heterochromatin of pluripotent stem cells is structurally distinct from that of lineage committed somatic cells. Furthermore, satellite RNA upregulation appears temporally linked to maturation of "somatic type" heterochromatin, suggesting a potential functional link. In Aim 2, satellite RNAs will be examined in cancer, based on unpublished findings showing gross overexpression of satellite II RNA in many cancer samples. It is well known that epigenetic changes can be important in cancer, but studies have focused primarily on inappropriate silencing (methylation) of tumor suppressor genes. While pathologists have long noted the loss of heterochromatic organization and satellite methylation in cancer, misregulation of satellite RNAs has not been specifically studied. A survey of cancer cell lines and cancer tissue types will be analyzed for overexpression of satellite RNA with a priority to establish this as a common hallmark of cancer and to ultimately determine the subset of expressing loci ("satellite RNA signature") in specific cancer subtypes and stages. Changes in satellite expression would comprise an essentially unknown but potentially important aspect of cancer cell biology, with direct implication for both epigenetic and genetic instability. Over the longer-term, the robust "satellite RNA signature" observed within cancer samples may serve as a biomarker for early detection and prognosis of cancer.
PUBLIC HEALTH RELEVANCE: The proposed research sets out to advance the knowledge of the structural changes that occur to individual cells upon the initiation and progression of cancer. The combined approach of using human embryonic stem cells in conjunction with cancer cell lines and tumor samples will allow for an in-depth analysis of the relationship between satellite DNA and structural changes in cellular reorganization. An understanding of how these events may be initiated will allow for a greater understanding of how and why cancer progresses.
描述(由申请人提供):近50%的人类基因组由非编码DNA元件组成,包括染色体中心和中心周围区域的几种类型的串联卫星重复序列。虽然卫星蛋白长期以来被认为是沉默的,但最近的证据表明,卫星蛋白重复序列可以表达,但其表达的程度和调控或其潜在功能仍有待阐明。由于它们位于对细胞分裂至关重要的区域内,预计这些序列的严格调控对表观遗传和遗传稳定性都是必不可少的。这项提议将建立在强有力的初步结果之上,这些结果表明卫星RNA调控可能对干细胞和癌细胞生物学都很重要。目的1将进一步建立在初步数据的基础上,即在胚胎干细胞分化过程中,着丝粒卫星的表达上调。令人惊讶的是,我们最近的研究结果还表明,多能干细胞的着丝粒异染色质在结构上不同于谱系的体细胞。此外,卫星RNA上调似乎暂时与“体细胞型”异染色质的成熟有关,这表明存在潜在的功能联系。在Aim 2中,卫星RNA将在癌症中进行研究,基于未发表的发现,在许多癌症样本中显示卫星II RNA的总体过表达。众所周知,表观遗传变化在癌症中可能很重要,但研究主要集中在肿瘤抑制基因的不适当沉默(甲基化)上。虽然病理学家早就注意到癌症中异染色质组织和卫星甲基化的缺失,但卫星rna的错误调节尚未得到专门研究。对癌细胞系和癌症组织类型的调查将分析卫星RNA的过表达,重点是将其确定为癌症的共同标志,并最终确定特定癌症亚型和分期中的表达位点子集(“卫星RNA特征”)。卫星表达的变化将包括癌细胞生物学中一个本质上未知但潜在重要的方面,对表观遗传和遗传不稳定性都有直接影响。从长期来看,在癌症样本中观察到的强大的“卫星RNA特征”可能作为癌症早期检测和预后的生物标志物。
项目成果
期刊论文数量(0)
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Dawn M. Carone其他文献
Probing nuclear HSATII biomolecular condensates
- DOI:
10.1016/j.bpj.2023.11.1388 - 发表时间:
2024-02-08 - 期刊:
- 影响因子:
- 作者:
Thembalami Dube;Christina A. Rabeler;Dawn M. Carone - 通讯作者:
Dawn M. Carone
Demethylated HSATII DNA And HSATII RNA Foci Sequester PRC1 Demethylated HSATII DNA And HSATII RNA Foci Sequester PRC1 And MeCP2 Into Cancer-Specific Nuclear Bodies And MeCP2 Into Cancer-Specific Nuclear Bodies
去甲基化 HSATII DNA 和 HSATII RNA 焦点隔离器 PRC1 去甲基化 HSATII DNA 和 HSATII RNA 焦点隔离器 PRC1 和 MeCP2 进入癌症特异性核体,MeCP2 进入癌症特异性核体
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
L. L. Hall;M. Byron;Dawn M. Carone - 通讯作者:
Dawn M. Carone
Centromere Conversion and Retention in Somatic Cell Hybrids
体细胞杂交体中着丝粒的转化和保留
- DOI:
10.1159/000328830 - 发表时间:
2011 - 期刊:
- 影响因子:1.7
- 作者:
Judith D. Brown;Dawn M. Carone;B. L. Flynn;C. E. Finn;E. E. Mlynarski;Rachel J. O’Neill - 通讯作者:
Rachel J. O’Neill
Human XIST RNA acts early to condense architecture which facilitates A-repeat density-dependent initiation of gene silencing
人类 XIST RNA 早期起作用以压缩结构,从而促进 A 重复密度依赖性基因沉默的启动
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
Melvys Valledor;M. Byron;B. Dumas;Dawn M. Carone;Lisa L. Hall;J. Lawrence - 通讯作者:
J. Lawrence
The role of ncRNA in centromeres: a lesson from marsupials.
ncRNA 在着丝粒中的作用:有袋动物的教训。
- DOI:
10.1007/978-3-642-00182-6_4 - 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
R. O’Neill;Dawn M. Carone - 通讯作者:
Dawn M. Carone
Dawn M. Carone的其他文献
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{{ truncateString('Dawn M. Carone', 18)}}的其他基金
Functional Analysis of Locus-Specific Pericentric Satellite Expression
位点特异性周中心卫星表达的功能分析
- 批准号:
9813265 - 财政年份:2019
- 资助金额:
$ 4.76万 - 项目类别:
Heterochromatin instability and misregulation of noncoding RNA in cancer
癌症中异染色质的不稳定性和非编码 RNA 的失调
- 批准号:
8391738 - 财政年份:2010
- 资助金额:
$ 4.76万 - 项目类别:
Heterochromatin instability and misregulation of noncoding RNA in cancer
癌症中异染色质的不稳定性和非编码 RNA 的失调
- 批准号:
8201093 - 财政年份:2010
- 资助金额:
$ 4.76万 - 项目类别:
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